GLUT2 Accumulation in Enterocyte Apical and Intracellular Membranes
A Study in Morbidly Obese Human Subjects and ob/ob and High Fat–Fed Mice
- Amal Ait-Omar1,
- Milena Monteiro-Sepulveda1,
- Christine Poitou2,3,
- Maude Le Gall1,
- Aurélie Cotillard2,
- Jules Gilet1,
- Kevin Garbin1,
- Anne Houllier1,
- Danièle Château1,
- Amélie Lacombe4,
- Nicolas Veyrie2,5,
- Danielle Hugol6,
- Joan Tordjman2,
- Christophe Magnan4,
- Patricia Serradas1,
- Karine Clément2,3,
- Armelle Leturque1 and
- Edith Brot-Laroche1⇓
- 1INSERM, U872, Team 9, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, Paris, France
- 2INSERM, U872, Team 7 Nutriomique, Paris, France; Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, UMR S 872, Paris, France
- 3 Nutrition and Endocrinology Department, Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France; Centre Recherche en Nutrition Humaine (CRNH) Ile de France, Paris, France
- 4Centre National de la Recherche Scientifique (EAC4413), Université Paris-Diderot, Paris, France
- 5Surgery Department, Assistance Publique-Hôpitaux de Paris, Hôtel-Dieu Hospital, Paris, France
- 6Pathology Department, Assistance Publique-Hôpitaux de Paris, Hôtel-Dieu Hospital, Paris, France
- Corresponding author: Edith Brot-Laroche, .
A.A.-O., M.M.-S., and C.P. contributed equally to this work.
OBJECTIVE In healthy rodents, intestinal sugar absorption in response to sugar-rich meals and insulin is regulated by GLUT2 in enterocyte plasma membranes. Loss of insulin action maintains apical GLUT2 location. In human enterocytes, apical GLUT2 location has not been reported but may be revealed under conditions of insulin resistance.
RESEARCH DESIGN AND METHODS Subcellular location of GLUT2 in jejunal enterocytes was analyzed by confocal and electron microscopy imaging and Western blot in 62 well-phenotyped morbidly obese subjects and 7 lean human subjects. GLUT2 locations were assayed in ob/ob and ob/+ mice receiving oral metformin or in high-fat low-carbohydrate diet–fed C57Bl/6 mice. Glucose absorption and secretion were respectively estimated by oral glucose tolerance test and secretion of [U-14C]-3-O-methyl glucose into lumen.
RESULTS In human enterocytes, GLUT2 was consistently located in basolateral membranes. Apical GLUT2 location was absent in lean subjects but was observed in 76% of obese subjects and correlated with insulin resistance and glycemia. In addition, intracellular accumulation of GLUT2 with early endosome antigen 1 (EEA1) was associated with reduced MGAT4a activity (glycosylation) in 39% of obese subjects on a low-carbohydrate/high-fat diet. Mice on a low-carbohydrate/high-fat diet for 12 months also exhibited endosomal GLUT2 accumulation and reduced glucose absorption. In ob/ob mice, metformin promoted apical GLUT2 and improved glucose homeostasis. Apical GLUT2 in fasting hyperglycemic ob/ob mice tripled glucose release into intestinal lumen.
CONCLUSIONS In morbidly obese insulin-resistant subjects, GLUT2 was accumulated in apical and/or endosomal membranes of enterocytes. Functionally, apical GLUT2 favored and endosomal GLUT2 reduced glucose transepithelial exchanges. Thus, altered GLUT2 locations in enterocytes are a sign of intestinal adaptations to human metabolic pathology.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db10-1740/-/DC1.
- Received December 15, 2010.
- Accepted July 31, 2011.
- © 2011 by the American Diabetes Association.
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